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A subpopulation of nociceptors specifically linked to itch

Abstract

Itch-specific neurons have been sought for decades. The existence of such neurons has been doubted recently as a result of the observation that itch-mediating neurons also respond to painful stimuli. We genetically labeled and manipulated MrgprA3+ neurons in the dorsal root ganglion (DRG) and found that they exclusively innervated the epidermis of the skin and responded to multiple pruritogens. Ablation of MrgprA3+ neurons led to substantial reductions in scratching evoked by multiple pruritogens and occurring spontaneously under chronic itch conditions, whereas pain sensitivity remained intact. Notably, mice in which TRPV1 was exclusively expressed in MrgprA3+ neurons exhibited itch, but not pain, behavior in response to capsaicin. Although MrgprA3+ neurons were sensitive to noxious heat, activation of TRPV1 in these neurons by noxious heat did not alter pain behavior. These data suggest that MrgprA3 defines a specific subpopulation of DRG neurons mediating itch. Our study opens new avenues for studying itch and developing anti-pruritic therapies.

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Figure 1: Generation of the Mrgpra3GFP-Cre transgenic mouse line.
Figure 2: Characterization of MrgprA3+ neurons.
Figure 3: MrgprA3+ DRG neurons form synaptic connections with GRPR+ neurons in the dorsal spinal cord.
Figure 4: MrgprA3+ neurons have polymodal nociceptors with C fibers and respond to multiple pruritogens.
Figure 5: The ablation of MrgprA3+ neurons.
Figure 6: Specific activation of MrgprA3+ neurons.
Figure 7: Specific activation of MrgprA3+ neurons evokes robust scratching and little or no pain response.

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Acknowledgements

We thank C. Hawkins and the staff of Transgenic Mouse Core at Johns Hopkins University School of Medicine for assistance with BAC transgenic mouse generation. We thank D. Anderson (California Institute of Technology) and M. Zylka (University of North Carolina at Chapel Hill) for providing MrgprdGFP/+ mice and A. Guler (University of Washington) for providing Rosa26Trpv1 mice. The work was supported by grants from the US National Institutes of Health to X.D. (NS054791 and GM087369), R.L. (NS047399 and NS014624) and Y.G. (NS070814). X.D. is an Early Career Scientist of the Howard Hughes Medical Institute.

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L.H. generated the Mrgpra3GFP-Cre mice, carried out the genetic manipulation and most of the behavioral, immunostaining and Ca2+ imaging experiments, and wrote the manuscript. C.M., H.N. and L.Q. conducted in vivo DRG recordings. Q.L., H.-J.W. and K.N.P. contributed to behavioral experiments. Y.C. and B.X. made the MrgprA3-Cre BAC construct. Z.T., Y.K. and Z.L. conducted in vitro DRG recordings. B.M., S.H. and Y.G. contributed to immunostaining experiments. R.L. and X.D. supervised the project and wrote the manuscript.

Corresponding authors

Correspondence to Robert H LaMotte or Xinzhong Dong.

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The authors declare no competing financial interests.

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Han, L., Ma, C., Liu, Q. et al. A subpopulation of nociceptors specifically linked to itch. Nat Neurosci 16, 174–182 (2013). https://doi.org/10.1038/nn.3289

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